Hyponatremia, a relative excess of total body water, is the most frequently encountered electrolyte abnormality; it's especially common among the elderly, the acutely and chronically ill, and among patients taking certain medications. Even a modest water excess (i.e., a modest reduction in plasma sodium concentration) is associated with substantial morbidity and mortality. Rare mutations in water- regulatory genes cause Mendelian disorders of water balance; however, these account for only a small minority of cases of hyponatremia. Our preliminary data show that the plasma sodium concentration is highly individual. That is, water balance differs between healthy unrelated individuals but is relatively constant over time in any one individual. We applied this principle to show that plasma sodium concentration is heritable. We refined this trait to eliminate or reduce the contribution of non-genetic factors (e.g., medications and co-morbidities). In genome-wide association analyses, a gene of high biological plausibility but not previously linked to systemic water balance associated with this phenotype. No prior studies have addressed the genetics of water balance on a population-wide basis, and there is at present no way to predict who is at greatest risk of developing hyponatremia in response to predisposing medications or disease states. The over-arching objective of this proposal is to define the population genetics of systemic water balance using data derived from prior large-scale NHLBI-sponsored (and other) cohort studies. In Aim 1, we will expand and replicate our discovery-phase meta-genome-wide association study on water balance using data from NHLBI-funded and international population-based cohorts. Our prior efforts led to our association of this phenotype with common variants in a gene of great interest and high biological plausibility, but not previously linked to this important clinical phenotype. In Aim 2, we will investigate the role of rare variants in this candidate water-balance gene in dysnatremic individuals and families, and in the dysnatremic extremes of NHLBI-funded and other population-based cohorts. In Aim 3, we seek to establish that our lead variant - a common polymorphism in a key regulatory region of this gene - represents the causal variant, based upon its location within the gene, the motif it impacts, and the known molecular mechanisms through which this gene is regulated.